Novel Risk Factors for Vertebral Fractures in Health and Chronic Kidney Disease

描述(申请人提供)：椎骨是成人最常见的骨折部位，使椎体骨折(VF)成为一个主要的公共卫生问题。由于与肾功能下降相关的骨骼和矿物质代谢紊乱，慢性肾脏疾病(CKD)患者特别容易发生骨折，与普通人群相比，骨折发生率较高。然而，在普通人群和患有CKD的个体中，对可改变的VF危险因素知之甚少。此外，目前评估骨健康的非侵入性临床参数未能准确预测CKD患者的骨折风险。这份K23提案将研究VF的新的可修改的危险因素，并探索无创成像方式在VF风险评估中的潜在作用。利用护士健康研究I和II的独特优势，包括提供高统计能力的大样本容量、长时间的随访期、丰富、有效的饮食和生活方式 我们将前瞻性地研究女性的饮食和生活方式因素与室颤风险(目标1)。椎体畸形是VF的重要预测因子，但目前尚无CKD患者椎体畸形的前瞻性纵向数据。我们将建立CKD患者和对照的队列，并前瞻性地跟踪脊柱畸形的发展/进展(目标2)。脊椎畸形将通过脊柱骨折评估进行评估，该评估使用X射线吸收法对侧椎进行成像，是一种可靠和准确的技术，可用于识别脊柱变形和室颤，具有辐射暴露低的优势。在我们的研究参与者中，我们将检查血清碳酸氢盐水平与脊柱畸形随时间的变化之间的关系。目前的成像技术无法测量骨基质或矿化，这可能在骨折风险中发挥重要作用。我们将使用新颖、创新的磁共振成像技术、固态(31P)和水和脂肪抑制的质子投影(1H WASPI)磁共振成像技术研究慢性肾脏病患者和对照组手腕的骨矿和基质含量(目标3)。骨基质和矿物质含量的非侵入性测量将提供有关患者骨骼质量和强度的内在属性的重要信息，而目前的成像技术无法提供这些信息。这项研究提案的结果将具有重要的临床意义，因为它将提高我们对VF危险因素及其评估的理解，从而使我们能够开发预防骨折及其后遗症的干预措施。这份申请是为了授予Julie Paik，医学博士，公共卫生硕士，MSc，她是布里格姆妇女医院(BWH)的一名肾病学家，在以患者为导向的骨骼和矿物质代谢临床研究中确立了自己的年轻研究员地位。她的长期目标是通过研究可改变的危险因素并努力优化他们的脊柱健康和预防骨折来改善CKD患者的脊柱健康。这项K23奖项将为白博士提供支持，以开发进行流行病学(目标1)和以患者为导向(目标2和3)临床研究所需的方法学工具和研究经验，并从长远来看成为一名独立的临床研究人员。这项建议利用了哈佛医学院丰富的资源和基础设施，包括BWH钱宁网络医学部、贝丝以色列女执事医疗中心(BIDMC)的哈佛催化剂临床研究中心(BIDMC)和马萨诸塞州总医院(MGH)的Martinos生物医学成像中心。Paik博士的研究工作将由她在BWH的导师Gary Curhan医学博士和ScD教授密切指导，Gary Curhan是哈佛医学院的医学教授和哈佛公共卫生学院的流行病学教授，他是一位著名的肾病学家和流行病学家，拥有开展创新研究和指导Paik博士等调查人员的丰富经验。他对导师的承诺从美国国立卫生研究院颁发的K24奖项中可见一斑。Curhan博士的专业知识和经验将得到一个咨询委员会的补充，该委员会由致力于Paik博士研究工作的资深研究人员组成：凯瑟琳·戈登，医学博士，理学硕士，儿科内分泌学家，代谢性骨疾病高级临床研究调查员，孩之宝儿童医院青少年医学部主任；哈罗德·罗森，医学博士，在骨质疏松症、骨健康和临床密度测量方面具有临床专业知识，并担任BIDMC骨质疏松预防和治疗中心主任；杰罗姆·阿克曼博士，麻省理工学院马蒂诺斯中心生物材料实验室主任，从事固态核磁共振研究40多年，并领导麻省理工学院固态核磁共振项目28年。为了扩大她的研究技能，白雪公主将在哈佛大学公共卫生学院学习生物统计学和流行病学方面的高级课程。此外，她还将出席BWH网络医学和肾脏科钱宁部的会议和研讨会，以及哈佛大学范围内关于代谢性骨骼疾病的研讨会和会议。通过这份K23提案的不同部分，包括研究提案、Curhan博士和其他咨询委员会成员的直接指导、哈佛公共卫生学院的高级课程以及一家主要研究和教学机构不同部门的大量会议和研讨会，白博士将能够成功地进一步发展和完善她的研究技能，并朝着她成为骨骼和矿物质代谢领域的独立临床研究员的目标努力。

DESCRIPTION (provided by applicant): The vertebra is the most common fracture site in adults, making vertebral fractures (VF) a major public health problem. Because of the bone and mineral metabolism derangements associated with declining kidney function, people with chronic kidney disease (CKD) are particularly vulnerable to developing fractures, with elevated fracture rates compared to the general population. However, little is known about modifiable VF risk factors, both in the general population and in individuals with CKD. Also, current non-invasive clinical parameters to assess bone health fail to predict fracture risk in CKD patients accurately. This K23 proposal will investigate novel modifiable risk factors for VF and explore the potential role of non- invasive imaging modalities in VF risk assessment. Taking advantage of the unique strengths of the Nurses' Health Studies I and II including large sample sizes providing high statistical power, long follow-up period, rich, well-validated dietary and lifestyle information, and VF cases confirmed by medical record, we will prospectively study dietary and lifestyle factors and VF risk in women (Aim 1). Vertebral deformities are important predictors of VF, but there are no prospective longitudinal data on vertebral deformities in CKD patients. We will establish a cohort of CKD patients and controls and prospectively follow the development/ progression of vertebral deformities over time (Aim 2). Vertebral deformities will be assessed by vertebral fracture assessment, which images the lateral spine using x-ray absorptiometry, and is a reliable and accurate technique for identifying vertebral deformities and VF with the advantage of low radiation exposure. Amongst our study participants with CKD, we will examine the association between serum bicarbonate level and change in vertebral deformities over time. Current imaging techniques are unable to measure the bone matrix or mineralization, which may play important roles in fracture risk. We will study the bone mineral and matrix content using novel, innovative MR imaging techniques, solid-state (31P) and water- and fat-suppressed proton projection (1H WASPI) MRI in the wrists of patients with CKD and controls (Aim 3). A non-invasive measure of bone matrix and mineral content would provide important information on the intrinsic properties of a patient's bone quality and strength that no current imaging technique is able to provide. Results from this research proposal will have important clinical implications by improving our understanding of VF risk factors and their assessment, thus enabling the development of interventions to prevent fractures and their sequelae. This application is for a K23 award for Julie Paik, MD, MPH, MSc, a nephrologist at Brigham and Women's Hospital (BWH), who is establishing herself as a young investigator in patient-oriented clinical research in bone and mineral metabolism. Her long-term goal is to improve the spinal health of patients with CKD by studying modifiable risk factors and working to optimize their spinal health and prevent fractures. This K23 award will provide Dr. Paik with the support to develop the methodologic tools and research experience necessary to conduct epidemiologic (Aim 1) and patient-oriented (Aims 2 and 3) clinical research, and in the long-term to become an independent clinical investigator. This proposal takes advantage of the rich resources and infrastructure at Harvard Medical School, including the Channing Division of Network Medicine, BWH, the Harvard Catalyst Clinical Research Center at Beth Israel Deaconess Medical Center (BIDMC), and the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH). Dr. Paik's research efforts will be closely guided by her mentor at BWH, Gary Curhan, MD, ScD, Professor of Medicine at Harvard Medical School and Epidemiology at the Harvard School of Public Health, a renowned nephrologist and epidemiologist who has extensive experience conducting innovative research and mentoring investigators such as Dr. Paik. His commitment to mentorship is evidenced by a K24 award from the NIH. Dr. Curhan's expertise and experience will be complemented by an advisory committee comprised of accomplished investigators who are all committed to Dr. Paik's research efforts: Catherine Gordon, MD, MSc, a pediatric endocrinologist, senior clinical research investigator in metabolic bone disease, and Chief of the Division of Adolescent Medicine at Hasbro Children's Hospital; Harold Rosen, MD, an endocrinologist with clinical expertise in osteoporosis, bone health, and clinical densitometry and Director of the Osteoporosis Prevention and Treatment Center at BIDMC; and Jerome Ackerman, PhD, Director of the Biomaterials Laboratory at the MGH Martinos Center, who has been conducting research on solid state MR for over 40 years and has led the solid state MR program at MGH for 28 years. To expand her research skills, Dr. Paik will take advanced coursework in biostatistics and epidemiology at the Harvard School of Public Health. In addition, she will attend conferences and seminars within BWH's Channing Division of Network Medicine and Renal Division, and Harvard-wide seminars and conferences on metabolic bone disease. Through the different components of this K23 proposal, including the research proposal, direct mentorship by Dr. Curhan and the other Advisory Committee members, advanced coursework at the Harvard School of Public Health, and wealth of conferences and seminars within the different divisions of a major research and teaching institution, Dr. Paik will be able to successfully further develop and refine her research skills and work towards her goal of becoming an independent clinical investigator in the field of bone and mineral metabolism.